Use of low dose amount of spironolactone for treatment of cardiovascular disease

ABSTRACT

Use of low dosages of an aldosterone receptor antagonist, spironolactone, is described for treatment of circulatory disorders. This therapy would be particularly useful to treat or retard the development of congestive heart failure, while avoiding or reducing aldosterone-antagonist-induced side effects, such as hyperkalemia.

FIELD OF THE INVENTION

[0001] Spironolactone, an aldosterone receptor antagonist, is describedfor use in treatment of circulatory disorders, including cardiovasculardiseases such as heart failure, hypertension and congestive heartfailure. Of particular interest is a therapy using spirolactone at a lowdosage at which side-effects are reduced or avoided.

BACKGROUND OF THE INVENTION

[0002] Myocardial (or cardiac) failure, that is, heart failure (“HF”),whether a consequence of previous myocardial infarction(s), heartdisease associated with hypertension, or primary cardiomyopathy, is amajor health problem of worldwide proportions. The incidence ofsymptomatic heart failure has risen steadily over the past severaldecades.

[0003] In clinical terms, decompensated cardiac failure consists of aconstellation of signs and symptoms that arise from congested organs andhypoperfused tissues to form congestive heart failure (CHF) syndrome.Congestion is caused largely by increased venous pressure and byinadequate sodium (Na⁺) excretion, relative to dietary Na⁺intake, and isimportantly related to circulating levels of aldosterone (ALDO). Anabnormal retention of Na⁺occurs via tubular epithelial cells throughoutthe nephron, including the later portion of the distal tubule andcortical collecting ducts, where ALDO receptor sites are present.

[0004] ALDO is the body's most potent mineralocorticoid hormone. Asconnoted by the term mineralocorticoid, this steroid hormone hasmineral-regulating activity. It promotes Na⁺reabsorption not only in thekidney, but also from the lower gastrointestinal tract and salivary andsweat glands, each of which represents classic ALDO-responsive tissues.ALDO regulates Na⁺and water resorption at the expense of potassium (K⁺)and magnesium (Mg²⁺) excretion.

[0005] ALDO can also provoke responses in non-epithelial cells. Elicitedby a chronic elevation in plasma ALDO level that is inappropriaterelative to dietary Na⁺ intake, these responses can have adverseconsequences on the structure of the cardiovascular system. Hence, ALDOcan contribute to the progressive nature of myocardial failure formultiple reasons.

[0006] Multiple factors regulate ALDO synthesis and metabolism, many ofwhich are operative in the patient with myocardial failure. Theseinclude renin as well as non-renin-dependent factors (such as K⁺, ACTH)that promote ALDO synthesis. Hepatic blood flow, by regulating theclearance of circulating ALDO, helps determine ALDO plasmaconcentration, an important factor in heart failure characterized byreduction in cardiac output and hepatic blood flow.

[0007] The renin-angiotensin-aldosterone system (“RAAS”) is one of thehormonal mechanisms involved in regulating pressure/volume homeostasisand also in the development of hypertension, a precursor conditonimplicated in the progression of more serious cardiovascular diseasessuch as congestive heart failure. Activation of therenin-angiotensin-aldosterone system begins with secretion of the enzymerenin from the juxtaglomerular cells in the kidney. The enzyme reninacts on a naturally-occurring substrate, angiotensinogen, to release adecapeptide, Angiotensin I. This decapeptide is cleaved by angiotensinconverting enzyme (“ACE”) to provide an octapeptide, Angiotensin II, theprimary active species of this system. This octapeptide, angiotensin II,is a potent vasoconstrictor and also produces other physiologicaleffects such as stimulating aldosterone secretion, promoting sodium andfluid retention, inhibiting renin secretion, increasing sympatheticnervous system activity, stimulating vasopressin secretion, causingpositive cardiac inotropic effect and modulating other hormonal systems.

[0008] Emphasis has been placed on minimizing hyperaldosteronism as abasis for optimizing patient treatment. This includes the importance ofALDO-receptor antagonism both in patients treated with conventionaldiuretic programs and in patients treated with angiotensin-convertingenzyme (ACE) inhibitors, who are often constrained to small doses of ACEinhibitor because of orthostatic hypotension. Such patients maydemonstrate a recurrence of heart failure symptoms likely related toelevations in plasma ALDO levels.

[0009] Many aldosterone receptor blocking drugs and their effects inhumans are known. For example, spironolactone is a drug which acts atthe mineralocorticoid receptor level by competitively inhibitingaldosterone binding. This steroidal compound has been used for blockingaldosterone-dependent sodium transport in the distal tubule of thekidney in order to reduce edema and to treat essential hypertension andprimary hyperaldosteronism [F. Mantero et al, Clin. Sci. Mol. Med., 45(Suppl 1), 219s-224s (1973)]. Spironolactone is also used commonly inthe treatment of other hyperaldosterone-related diseases such as livercirrhosis and congestive heart failure [F. J. Saunders et al, Aldactone;Spironolactone: A Comprehensive Review, Searle, New York (1978)].Progressively-increasing doses of spironolactone from 1 mg to 400 mg perday [i.e., 1 mg/day, 5 mg/day, 20 mg/day] was administered to aspironolactone-intolerant patient to treat cirrhosis-related ascites [P.A. Greenberger et al, N. Eng. Reg. Allergy Proc., 7(4), 343-345(July-August, 1986)]. It has been recognized that development ofmyocardial fibrosis is sensitive to circulating levels of bothAngiotensin II and aldosterone, and that the aldosterone antagonistspironolactone prevents myocardial fibrosis in animal models, therebylinking aldosterone to excessive collagen deposition [D. Klug et al, Am.J. Cardiol., 71(3), 46A-54A (1993)]. Spironolactone has been shown toprevent fibrosis in animal models irrespective of the development ofleft ventricular hypertrophy and the presence of hypertension [C. G.Brilla et al, J. Mol. Cell. Cardiol., 25(5), 563-575 (1993)].Spironolactone at a dosage ranging from 25 mg to 100 mg daily is used totreat diuretic-induced hypokalemia, when orally-administered potassiumsupplements or other potassium-sparing regimens are consideredinappropriate [Physicians' Desk Reference, 46th Edn., p. 2153, MedicalEconomics Company Inc., Montvale, N.J. (1992)].

[0010] Previous studies have shown that inhibiting ACE inhibits therenin-angiotensin system by substantially complete blockade of theformation of Angiotensin II. Many ACE inhibitors have been usedclinically to control hypertension. While ACE inhibitors may effectivelycontrol hypertension, side effects are common including chronic cough,skin rash, loss of taste sense, proteinuria and neutropenia.

[0011] Moreover, although ACE inhibitors effectively block the formationof Angiotensin II, aldosterone levels are not well controlled in certainpatients having cardiovascular diseases. For example, despite continuedACE inhibition in hypertensive patients receiving captopril, there hasbeen observed a gradual return of plasma aldosterone to baseline levels[J. Staessen et al, J. Endocrinol., 91, 457-465 (1981)]. A similareffect has been observed for patients with myocardial infarctionreceiving zofenopril [C. Borghi et al, J. Clin. Pharmacol., 33, 40-45(1993)]. This phenomenon has been termed “aldosterone escape”.

[0012] In a side-by-side treatment of two cohorts of rats, one cohorttreated with spironolactone sub-cutaneously and the other cohort treatedwith captopril, spironolactone was found to prevent fibrosis in thehypertensive-rat cohort [C. G. Brilla et al, J. Mol. Cell. Cardiol., 25,563-575 (1993)].

SUMMARY OF DRAWING FIGURES

[0013]FIG. 1 shows urinary aldosterone levels at different rates ofspironolactone administration (12.5 mg, 25 mg, 50 mg, 75 mg), ascompared to placebo, co-administered with stable doses of ACE inhibitorand loop diuretic.

[0014]FIG. 2 shows plasma renin activity at different rates ofspironolactone administration (12.5 mg, 25 mg, 50 mg, 75 mg), ascompared to placebo, co-administered with stable doses of ACE inhibitorand loop diuretic.

[0015]FIG. 3 shows N-Terminal ANF levels at different rates ofspironolactone administration (12.5 mg, 25 mg, 50 mg, 75 mg), ascompared to placebo, co-administered with stable doses of ACE inhibitorand loop diuretic.

[0016]FIG. 4 shows changes in supine blood pressure at different ratesof spironolactone administration (12.5 mg, 25 mg, 50 mg, 75 mg), ascompared to placebo, co-administered with stable doses of ACE inhibitorand loop diuretic.

[0017]FIG. 5 shows changes in supine heart rate at different rates ofspironolactone administration(12.5 mg, 25 mg, 50 mg, 75 mg), as comparedto placebo, co-administered with stable doses of ACE inhibitor and loopdiuretic.

DESCRIPTION OF THE INVENTION

[0018] Treatment or prevention of circulatory disorders, includingcardiovascular disorders such as heart failure, hypertension andcongestive heart failure, is provided by a therapy comprising use of atherapeutically-effective amount of spironolactone. Preferably,spironolactone is administered in the therapy at a low dose, that is, ata dose lower than has been conventionally used in clinical situations.

[0019] The therapy of the invention would be useful, for example, toprevent or retard, in a subject, the development of congestive heartfailure which typically arises from essential hypertension or from heartconditions following myocardial infarct. Such subject would nottypically be suffering from an edematous condition and thus would notgain benefit from treatment with conventional diuretic therapy as withloop diuretics which can alter electrolyte balance and cause hypokalemicor hypomagnesia conditions.

[0020] The phrase “aldosterone receptor antagonist” embraces an agent orcompound, or a combination of two or more of such agents or compounds,which agent or compound binds to the aldosterone receptor as acompetitive inhibitor of the action of aldosterone itself at analdosterone receptor site, such as typically found in the renal tubules,so as to modulate the receptor-mediated activity of aldosterone. Typicalof such aldosterone receptor antagonists are spirolactone-typecompounds. The term “spirolactone-type” is intended to characterize asteroidal structure comprising a lactone moiety attached to a steroidnucleus, typically at the steroid “D” ring, through a spiro bondconfiguration.

[0021] The phrase “therapeutically-effective” is intended to qualify theamount of aldosterone receptor antagonist agent for use in the therapywhich will achieve the goal of improvement in cardiac sufficiency byreducing or preventing, for example, the progression of congestive heartfailure, while avoiding adverse side effects typically associated withsuch agent.

[0022] The phrase “low-dose amount”, in characterizing atherapeutically-effective amount of the aldosterone receptor antagonistagent in the combination therapy, is intended to define a quantity ofsuch agent, or a range of quantity of such agent, that is capable ofimproving cardiac sufficiency while reducing or avoiding one or morealdosterone-antagonist-induced side effects, such as hyperkalemia. Adosage of spironolactone which would accomplish the therapic goal offavorably enhancing cardiac sufficiency, while reducing or avoiding sideeffects, would be a dosage that substantially avoids inducing diuresis,that is, a substantially non-diuresis-effective dosage.

[0023] The compound spironolactone has the following structure andformal name:

[0024] Methods to make spironolactone are described in U.S. Pat. No.3,013,012 to Cella et al which issued Dec. 12, 1961. Spironolactone issold by G. D. Searle & Co., Skokie, Ill., under the trademark“ALDACTONE”, in tablet dosage form at doses of 25 mg, 50 mg and 100 mgper tablet.

[0025] A diuretic agent may be used in combination with spironolactone.Such diuretic agent may be selected from several known classes, such asthiazides and related sulfonamides, potassium-sparing diuretics, loopdiuretics and organic mercurial diuretics.

[0026] Examples of thiazides are bendroflumethiazide, benzthiazide,chlorothiazide, cyclothiazide, hydrochlorotthiazide, hydroflumethiazode,methyclothiazide, polythiazide and trichlormethiazide.

[0027] Examples of related sulfonamides are chlorthalidone, quinethazoneand metolazone.

[0028] A diuretic agent may be used in combination with spironolactone.Such diuretic agent may be selected from several known classes, such asthiazides and related sulfonamides, potassium-sparing diuretics, loopdiuretics and organic mercurial diuretics.

[0029] Examples of thiazides are bendroflumethiazide, benzthiazide,chlorothiazide, cyclothiazide, hydrochlorothiazide, hydroflumethiazide,methyclothiazide, polythiazide and trichlormethiazide.

[0030] Examples of sulfonamides related to thiazides are chlorthalidone,quinethazone and metolazone.

[0031] Examples of potassium-sparing diuretics are triameterene andamiloride.

[0032] Examples of loop diuretics, i.e., diuretics acting in theascending limb of the loop of Henle of the kidney, are furosemide andethynacrylic acid.

[0033] Examples of organic mercurial diuretics are mercaptomerin sodium,merethoxylline procaine and mersalyl with theophylline.

Biological Evaluation Human Clinical Trials

[0034] Spironolactone was evaluated in humans as described in thefollowing clinical trials.

[0035] Patients: Two-hundred fourteen (214) patients with symptomaticheart failure had an ejection fraction ≦35%, a history of New York HeartAssociation (NYHA) functional classification III-IV six months prior toenrollment, and current classification II-IV were randomized among fivetreatment groups. Patients were assigned to receive eitherspironolactone 12.5 mg (41 patients), 25 mg (45 patients), 50 mg (47patients), 75 mg (41 patients), or placebo (40 patients) once a day for12 weeks. Two patients that were randomized failed to take the studymedication and were excluded from the analysis. All patients were takinga stable dose of ACE inhibitor, loop diuretic, and optional digitalisfor 30 days prior to the first dose of study medication. Potassiumsupplement therapy that was stable for 14 days prior to the first doseof study medication was also allowed. Informed consent was obtained fromall patients, and the protocol was approved by each ethical committee.At enrollment all patients had normal serum potassium values (<5.5mmol/L) and creatinine values of ≦2.0 mg/dL or ≦180 mmol/L. Patientswere excluded from enrollment if they: (1) were diagnosed with either anacute life-threatening disease (included patients with automaticimplantable cardioverter/defibrillator), valvular disease, unstableangina, insulin-dependent diabetes, cancer (without a reoccurrencewithin the last five years), or primary hepatic failure; (2) were on awaiting list for a heart transplant or experienced a myocardialinfarction 30 days prior to the first dose of study medication; (3) hadlaboratory values for hematology or biochemistry considered abnormal andclinically significant prior to the first dose of study medication; (4)received a potassium spacing diuretic within 30 days prior to the firstdose of study medication.; (5) were receiving, on a regular basis,either non-steroidal anti-inflammatory drugs or aspirin>325 mg/day,steroids, dopamine agonists or antagonists, insulin or heparin; (6) wereon any investigational medication within 30 days of the first dose ofmedication.

[0036] Study Design: This was a multinational, double-blind, randomized,parallel group study.

[0037] Laboratory Measurements: The following information was obtainedfrom each patient at baseline:

[0038] 1. Concurrent medication within the past 30 days.

[0039] 2. 12-lead ECG

[0040] 3. Cardiac assessments that included blood pressure, pulse,sodium retention score (general assessment of a patient's edematousstate was derived from the summation of scores obtained from Table I),NYHA classification, and

[0041] 4. Signs and symptoms within the past 30 days. TABLE I SodiumRetention Score Parameters Grade Assessment Rales 0 Absent 1 In lower ⅓of lungs 2 In lower ⅔ of lungs 3 In all lung fields Peripheral 0 AbsentPitting Edema 1 Trace 2 Limited to ankles 3 Not limited to ankles 4Anasarca Weight Change −1 Decreased 0 Unchanged 1 Increased Hepatomegaly0 Absent 1 Present S3 Gallop 0 Absent 1 Present Increased Jugular 0Absent Venous Pressure 1 Present

[0042] The following laboratory values were obtained at the pretreatmentvisit:

[0043] Hematology: White blood cell count (WBC), hematocrit, hemoglobin,platelet count.

[0044] Biochemistry: Creatinine, potassium, AST, SGOT, urinarysodium/potassium ratio, bicarbonate, calcium, chloride, creatinine,creatinine clearance, magnesium, glucose, urea, uric acid.

[0045] Neurohormones: Plasma renin activity, pro-atrial natriureticfactor, urinary aldosterone.

[0046] Blood and urine samples were centrally analyzed at SciCorLaboratories. Laboratory values for urinary aldosterone and renin levelswere done at the Ohio State University Laboratory in Columbus, Ohio.Pro-atrial natriuretic factor samples were evaluated at the Universityof Oslo Laboratory in Oslo, Norway. Patients were evaluated 9 days afterbeginning study medication. Documented changes in concurrentmedications, signs and symptoms and drug compliance were recorded. Theseprocedures were repeated at Week 4 and Week 8 visits. Patientinformation and procedures on the final visit (Week 12) was identical tothe pre-treatment visit.

[0047] Statistical Analysis: Analysis of cardiac assessment changes inpatient therapy and vital signs were performed for both theIntent-to-Treat (ITT) and evaluable patient groups. Analysis ofdemographic variables, adverse events and clinical laboratory valueswere performed in the ITT group. For each efficacy variable, results ofeach visit were examined separately. An appropriate trend test was usedto test for overall dose-response. Pair-wise comparisons were made foreach active dose to placebo. Significant levels for pair-wisecomparisons were adjusted using the Hochberg-Bonferromi method tomaintain the overall Type I error rate. All statistical methods weretwo-sided.

[0048] Recruitment: Two-hundred and fourteen patients were recruitedfrom 22 study sites in eleven countries.

[0049] Patient Characteristics: Patient demographic, vital signs, andcardiac status at baseline are summarized in Table II. TABLE II PatientDemographics Spironolactone Spironolactone Spironolactone Spironolactonep- Demographic 12.5 mg/d 25 mg/d 50 mg/d 75 mg/d Placebo Value Age(years) 63 ± 12 61 ± 9  62 ± 13 62 ± 13 61 ± 12 N.S. Caucasian/other (%)93/7  98/2  93/7  88/12 97/3  N.S. Male/female (%) 78/22 82/18 74/2688/12 83/18 N.S. Vital Signs Weight (kg) 74 75 73 78 73 N.S. Bloodpressure (mmHg) Systolic 121 120 121 125 121 N.S. Diastolic 76 76 75 8174 N.S. Pulse (bpm) 76 74 76 74 71 N.S. Cardiac Status NYHA (%) II 63 6043 49 38 III 34 38 55 49 60 IV 2 2 2 2 2 N.S. Sodium retention scoreMean value 1.54 1.62 1.64 1.61 1.78 N.S. ACE-I (Mean dose) Captopril(mg) 57.3 57.5 69.7 59.4 65.4 N.S. Enalapril (mg) 16.4 13.4 14.5 16.310.8 N.S. Loop Diuretic (Mean dose) Furosemide (mg) 58.8 82.8 76.9 84.963.2 N.S. Digoxin (%) 78.0 77.8 76.6 80.5 77.5 N.S. Potassium supplement(%) 43.9 37.8 34.0 39.0 30.0 N.S.

[0050] Patients ranged in age from 26 to 83 years (mean=60), 81% weremale, 94% were Caucasian. At baseline 51% of the patients were NYHAClass II, 47% were Class III. With respect to sodium retention score, astatistically significant dose response was seen at Day 9 with higherdoses showing more reduction in sodium retention score (p=0.019).However, this effect was not seen at later visits (p>0.20). There was animprovement in NYHA Class placebo group and in all the spironolactonegroups. Although a trend toward improvement in the spironolactone groupwas observed, the difference was not statistically significant.

[0051] Changes in Patient Therapy: The treatment groups did not differsignificantly with respect to changes in dose of ACE inhibitor,digitalis or potassium supplements at any visit (p≧0.11). The treatmentgroups did differ significantly with respect to changes in loop diuretictherapy only at Week 8 (p=0.004) in that more patients on the higherdoses of spironolactone had decreases in the loop diuretic dose comparedto the placebo group. This pattern was not observed at Week 12.

[0052] Changes in Vital Signs: Changes from baseline in vital signs atWeek 12 are summarized in Table III. TABLE III Mean Change in Weight andVital Signs from Baseline to Week 12 Spironolactone SpironolactoneSpironolactone Spironolactone p- 12.5 mg/d 25 mg/d 50 mg/d 75 mg/dPlacebo Value Weight 0.59 (3.00) −0.16 (3.02) 0.62 (2.05) −0.81 (2.70)0.11 (2.46) 0.109 Supine systolic BP 1.84 (11.82) −4.46 (13.97) −7.04(15.83) −5.68 (15.62) 0.22 (13.45) 0.036 Supine diastolic BP −0.19(9.13) −2.74 (9.57) −5.11 (11.11) −5.91 (9.05) 1.78 (7.84) 0.014 Supinepulse (BPM) −3.70 (9.56) −1.40 (10.00) −3.21 (11.27) −1.07 (13.79) 1.42(9.69) 0.422

[0053] At all visits the 25 mg, 50 mg, and 75 mg groups had decreases inmean systolic and diastolic blood pressure, while the placebo group hadincreases in mean systolic and diastolic blood pressure (both standingand supine). Dose response with respect to standing and supine diastolicblood pressure was statistically significant for all visits (p≦0.002).Dose response with respect to standing and supine blood pressure wasstatistically significant at Week 4, Week 8, and Week 12 (p≦0.033), butnot at Day 9 (p≧0.12). No significant between-treatment differences inchange from baseline in pulse were observed at any visit(p-values≧0.136). A statistically significant dose response with greaterdecreases in pulse in the supine position at higher doses was observedat Week 4 (p-value=0.045). Spironolactone doses of 25 and 50 mg werealso significantly different from placebo (p-values≦0.043) (See FIG. 1).At Day 9 and Week 4 visits, there was a statistically significant doseresponse with respect to changes from baseline in body weight in thatpatients in the 75 mg dose group experienced more weight loss than otherpatients. This dose response was not observed at later visits (p≧0.062).

[0054] Clinical Laboratory Values: Table IV contains details of thedifferent clinical laboratory values that showed statisticallysignificant treatment differences with respect to mean changes at Week12 visit compared with their respective baseline value. TABLE IV Week 12Mean Change Spironolactone Spironolactone Spironolactone Spironolactonep- 12.5 mg/d 25 mg/d 50 mg/d 75 mg/d Placebo Value Urinary aldosterone(nmol/D) 4.21 4.27 8.11 11.13 0.76 0.002 N-Terminal ANF (pmol/L) −287.30−294.60 −351.30 −370.60 54.50 0.022 PRA (NgAngl/L/s) 9.90 9.33 13.1810.23 0.50 0.002 Hematocrit (%) 0.00 −0.02 −0.02 −0.03 0.00 0.002Hemoglobin (mmol/L/Fe) 0.12 −0.20 −0.31 −0.46 0.00 0.005 Potassium(mmol/L) 0.18 0.37 0.51 0.58 −0.10 0.001 Creatinine (umol/L) 6.83 9.3014.06 21.90 −1.96 0.001 Sodium (mmol/L) −1.61 −1.85 −2.52 −3.37 −0.030.001

[0055] Urinary Aldosterone (See FIG. 2): Urinary aldosterone wasdetermined only for baseline and the 12 week visit. Urinary aldosteroneexcretion showed mean increases from baseline in all treatment groups(P≦0.012). Greater increases were seen at higher doses of spironolactone(p=0.002). All pair-wise comparisons between active treatment andplacebo were statistically significant (p≦0.009).

[0056] Plasma Renin Activity (PRA) (See FIG. 2): A statisticallysignificant dose-response with respect to change from baseline in PRAwas seen at Day 9, Week 4 and Week 12 (P≦0.001) with higher doses ofspironolactone associated with greater increases in PRA. PRA was notmeasured at Week 8.

[0057] N-Terminal Atrial Natriuretic Factor (ANF) (See FIG. 3): Allactive treatments showed decreases from baseline at all treatmentvisits. Dose-response was statistically significant at Day 9 (p=0.048),Week 4 (p=0.005), and Week 12 (p=0.008). ANF was not measured at Week 8.In comparisons the 50 mg dose group differed significantly from placeboat Week 4 (p=0.009) and Week 12 (p=0.006), while the 75 mg dose groupdiffered significantly from placebo at Week 12 only (p=0.007).

[0058] Hematocrit and Hemoglobin: At Day 9 visit a statisticallysignificant mean value difference between placebo and the differentactive treatments was observed with lower values for the placebo groupthan the active treatments (p<0.001). At Week 12 a reverse statisticallysignificant difference was observed with lower levels for the activetreatment groups for hematocrit (p=0.002) and hemoglobin (0.005).

[0059] Serum Potassium: A statistically significant dose-response withrespect to change from baseline in serum potassium was seen at alltreatment period visits (p<0.001). Higher doses of spironolactone wereassociated with larger increases in potassium. All doses of activetreatment had significantly higher serum potassium levels relative tobaseline than placebo (p≦0.034). Incidence of Hyperkalemia Spirono-Spirono- Spirono- lactone lactone lactone Spironolactone Treatment:Placebo 12.5 mg/d 25 mg/d 50 mg/d 75 mg/d Patients (%)2(5%) 2(5%) 6(13%)9(20%) 10(24%)

[0060] Predictors of Hyperkalemia: Seven possible predictors ofhyperkalemia (potassium≧5.5 mmol/L) were included in a step-wise Coxregression analysis: randomized treatment (treated as a categoricalvariable), age, baseline NYHA class, baseline serum potassium, baselinePRA, baseline creatinine, baseline urinary aldosterone, and type anddose of ACE-I. Besides the dose of spironolactone, the followingpredictors of hyperkalemia were statistically significant in thestep-wise regression analysis: type of ACE-I (captopril versus other),baseline serum creatinine, and baseline serum potassium. Results aresummarized as follows: Factor p-value Risk Ratio Captopril vs otherACE-I 0.013 0.318 Serum Creatinine > normal 0.038 2.72 BaselinePotassium > median 0.040 2.32

[0061] In this analysis, the risk ratio can be thought of as theprobability that the patient with the risk factor will develophyperkalemia, relative to the probability that a patient without therisk factor will develop it. (For example, patients on captopril areabout one-third as likely to develop hyperkalemia as a patient onanother ACE-I.)

[0062] Risk ratios relative to placebo for the various doses ofspironolactone are: Dose p-value Risk Ratio Spironolactone 12.5 mg 0.981.02 Spironolactone 25 mg 0.19 2.91 Spironolactone 50 mg 0.034 5.32Spironolactone 75 mg 0.016 6.66

[0063] After adjusting for the above factors, other predictors includedin the step-wise regression analysis were not significant(p-values≧0.07). However, the following additional factor wassignificantly related to the development of hyperkalemia when consideredapart from other predictors except the dose of spironolactone. Factorp-value Risk Ratio High ACE-I Dose 0.050 2.93

[0064] Serum Magnesium: Change from baseline in serum magnesium showed astatistically significant dose-response at Day 9 and Week 4 (p≦0.048),with more patients in the placebo group showing decreases in serummagnesium. However, this effect was not seen at later visits (p≧0.083).

[0065] Adverse Effects: Table V summarizes the twelve most commonadverse events by different treatment groups. Only one symptom,hyperkalemia, showed a clear dose-response in term of incidence(p=0.001). TABLE V Incidence of Adverse Events SpironolactoneDose-Ranging Study Intent-to-Treat Cohort (Top Twelve Events) TreatmentGroup (Percentage of Patients) Spironolactone SpironolactoneSpironolactone Spironolactone Adverse Events 12.5 mg 25 mg 50 mg 75 mgPlacebo Total Dyspnea 22.0 15.6 26.1 24.4 30.0 23.5 Angina Pectoris 19.520.0 8.7 14.6 17.5 16.0 Dizziness 12.2 13.3 13.0 17.1 15.0 14.1 Fatigue12.2 13.3 15.2 14.6 15.0 14.1 Nausea 2.4 17.8 6.5 19.5 12.5 11.7Diarrhea 4.9 22.2 8.7 14.6 5.0 11.3 Abdominal Pain 7.3 8.9 13.0 7.3 17.510.8 Headache 9.8 2.2 15.2 7.3 20.0 10.8 Hyperkalemia 2.4 8.9 15.2 19.52.5 9.9 URT Infection 4.9 11.1 8.7 2.4 12.5 8.0 Arthralgia 4.9 4.4 8.74.9 7.5 6.1 Coughing 4.9 2.2 4.3 2.4 12.5 5.2

[0066] A breakdown of the hospitalizations is as follows:

[0067] Treatment Placebo 12.5 mg 25 mg 50 mg 75 mg P

[0068] Patients (%) 5(12.5%) 3(7.3%) 3(6.6%) 13(27.6%) 6(14.6%) N.S.

[0069] No deaths were reported during the drug treatment period. Threepatients died within 30 days after the study was completed. These threepatients were previously at the 50 mg dose.

[0070] Administration of spironolactone may be accomplished by oralroute, or by intravenous, intramuscular or subcutaneous injections. If adiuretic is used in co-therapy, with spironolactone, then administrationmay take place sequentially in separate formulations, or may beaccomplished by simultaneous administration in a single formulation orseparate formulations. The formulation may be in the form of a bolus, orin the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solution and suspensions may be preparedfrom sterile powders or granules having one or morepharmaceutically-acceptable carriers or diluents, or a binder such asgelatin or hydroxypropyl-methyl cellulose, together with one or more ofa lubricant, preservative, surface-active or dispersing agent.

[0071] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. A suitable daily dose fora mammal may vary widely depending on the condition of the patient andother factors. Spironolactone may be present in an amount of from about1 to 400 mg, preferably from about 2 to 150 mg, depending upon thespecific ALDO antagonist compound selected and the specific diseasestate being targetted for the combination therapy. If a diuretic agentis used in co-therapy, then such agent may be present in an amount fromabout 1 mg to about 400 mg per dose, and more preferably from about 1 mgto about 150 mg per dose, depending on the diuretic selected.

[0072] For disease states which require prevention, reduction ortreatment of a cardiovascular disease state without incidence ofhyperkalemia, for example, spironolactone will be present in the therapyin an amount in a range from about 1 mg to about 25 mg per dose. Apreferred range for spirolactone would be from about 5 mg to 15 mg perdose. More preferably would be a range from about 10 mg to 15 mg perdose per day.

[0073] Examples of various ALDO antagonist daily doses of the inventionare as follow:

Spironolactone (mg)

[0074] 5

[0075] 7.5

[0076] 10

[0077] 12.5

[0078] 15

[0079] 17.5

[0080] 20

[0081] 22.5

[0082] The active ingredients may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier.

[0083] The dosage regimen for treating a disease condition with thecombination therapy of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex and medicalcondition of the patient, the severity of the disease, the route ofadministration, and the particular compound employed, and thus may varywidely.

[0084] For therapeutic purposes, the active components of thiscombination therapy invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the components may be admixed with lactose,sucrose, starch powder, cellulose esters of alkanoic acids, cellulosealkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide,sodium and calcium salts of phosphoric and sulfuric acids, gelatin,acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinylalcohol, and then tableted or encapsulated for convenientadministration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The components may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

[0085] Pharmaceutical compositions for use in the treatment methods ofthe invention may be administered in oral form or by intravenousadminstration. Oral administration of the therapy is preferred. Dosingfor oral administration may be with a regimen calling for single dailydose, or for a single dose every other day, or for multiple, spaceddoses throughout the day. Where a combination therapy is desired, forexample, an aldosterone antagonist and a diuretic, the active agentswhich make up the combination therapy may be administeredsimultaneously, either in a combined dosage form or in separate dosageforms intended for substantially simultaneous oral administration. Theactive agents which make up the combinatin therapy may also beadministered sequentially, with either active component beingadministered by a regimen calling for two-step ingestion. Thus, aregimen may call for sequential administration of the active agents withspaced-apart ingestion of the separate, active agents. The time periodbetween the multiple ingestion steps may range from a few minutes toseveral hours, depending upon the properties of each active agent such apotency, solubility, bioavailability, plasma half-life and kineticprofile of the agent, as well as depending upon the age and condition ofthe patient. The active agents of the combined therapy whetheradministered simultaneously, substantially simultaneously, orsequentially, may involve a regimen calling for administration of oneactive agent by oral route and the other active agent by intravenousroute. Whether the active agents of the combined therapy are adminsteredby oral or intravenous route, separately or together, each such activeagent will be contained in a suitable pharmaceutical formulation ofpharmaceutically-acceptable excipients, diluents or other formulationscomponents. Examples of suitable pharmaceutically-acceptableformulations containing the active components for oral administrationare given below. Even though such formulations list both active agentstogether in the same recipe, it is appropriate for such recipe to beutilized for a formulation containing one of the active components.

EXAMPLE 1

[0086] An oral dosage may be prepared by screening and then mixingtogether the following list of ingredients in the amounts indicated. Thedosage may then be placed in a hard gelatin capsule. Ingredients Amountsspironolactone 12.5 mg magnesium stearate   10 mg lactose  100 mg

EXAMPLE 2

[0087] An oral dosage may be prepared by mixing together granulatingwith a 10% gelatin solution. The wet granules are screened, dried, mixedwith starch, talc and stearic acid, screened and compressed into atablet. Ingredients Amounts spironolactone 12.5 mg calcium sulfatedihydrate 100 mg sucrose 15 mg starch 5 mg talc 4 mg stearic acid 2 mg

EXAMPLE 3

[0088] An oral dosage may be prepared by screening and then mixingtogether the following list of ingredients in the amounts indicated. Thedosage may then be placed in a hard gelatin capsule. Ingredients Amountsspironolactone 12.5 mg furosemide 73.9 mg magnesium stearate 10 mglactose 100 mg

EXAMPLE 4

[0089] An oral dosage may be prepared by mixing together granulatingwith a 10% gelatin solution. The wet granules are screened, dried, mixedwith starch, talc and stearic acid, screened and compressed into atablet. Ingredients Amounts spironolactone 12.5 mg furosemide 73.9 mgcalcium sulfate dihydrate 100 mg sucrose 15 mg starch 8 mg talc 4 mgstearic acid 2 mg

[0090] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A pharmaceutical dosage comprising one or morepharmaceutically-acceptable excipients and spironolactone in an amountwhich is therapeutically effective to antagonize aldosterone but whichamount is not sufficient to induce substantial diuresis.
 2. The dosageof claim 1 wherein said subject is afflicted with or susceptible tocongestive heart failure and said subject further requires avoidance ofthe incidence of hyperkalemia.
 3. The dosage of claim 1 whereinspironolactone is present in a dose range from about 1 mg to about 23mg.
 4. The dosage of claim 3 wherein spironolactone is present in a doserange of about 5 mg to about 20 mg.
 5. The dosage of claim 4 whereinspironolactone is present in a dose of about 12.5 mg.
 6. A method totreat a circulatory disorder in a subject in need therof, said methodcomprising administering to said subject an amount of spironolactonesufficient to prevent or retard the development of congestive heartfailure but less than an amount to induce incidence of hyperkalemia. 7.The method of claim 6 comprising administering spironolactone in anamount that substantially avoids inducing diuresis.
 8. The method ofclaim 7 comprising administering spironolactone in an amount less than25 mg per day.
 9. The method of claim 8 comprising administeringspironolactone in an amount from about 5 mg to about 20 mg per day. 10.The method of claim 8 comprising administering spironolactone in anamount from about 5 mg to about 15 mg per day.
 11. The method of claim 8comprising administering spironolactone in an amount of about 12.5 mgper day.